Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line

Clifford G Tepper, David L. Boucher, Philip E. Ryan, Ai Hong Ma, Liang Xia, Li Fen Lee, Thomas G. Pretlow, Hsing-Jien Kung

Research output: Contribution to journalArticle

211 Scopus citations

Abstract

CWR22 has been a valuable xenograft model for the study of prostate cancer progression from an androgen-dependent tumor to one that grows in castrated animals. Herein, we report the identification and characterization of a novel androgen receptor (AR) mutation occurring in a relapsed tumor (CWR22R-2152) and in the CWR22Rv1 cell line established from it. The mutation was not detected in the original, hormone-dependent CWR22 xenograft, indicating that this change occurred during the progression to androgen independence. It is characterized by an in-frame tandem duplication of exon 3 that encodes the second zinc finger of the AR DNA-binding domain. Accordingly, immunoblot analyses demonstrated the expression of an AR species having an approximately 5-kDa increase in size relative to the LNCaP AR. This was accompanied by a COOH-terminally truncated AR species migrating with a relative mass of 75-80 kDa, referred to as ARΔLBD because it lacks the ligand-binding domain. By recreating the exon 3 duplication mutation in a wild-type AR expression construct, the generation of ARΔLBD could be recapitulated. Whereas ARΔLBD exhibited constitutive nuclear localization and DNA binding, these functions in the full-length AR remained androgen dependent. The CWR22Rv1 AR repertoire displayed dose-dependent, androgen-responsive transcriptional transactivation in reporter assays, albeit to a lesser extent in comparison with LNCaP. This cell line also expressed low levels of prostate-specific antigen mRNA and did not express or secrete detectable levels of prostate-specific antigen protein in androgen-depleted medium or in response to physiological androgenic stimulation. In summary, the CWR22Rv1 cell line displays both androgen-responsive and androgen-insensitive features due, at least in part, to a novel insertional mutation of the AR.

Original languageEnglish (US)
Pages (from-to)6606-6614
Number of pages9
JournalCancer Research
Volume62
Issue number22
StatePublished - Nov 15 2002

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Tepper, C. G., Boucher, D. L., Ryan, P. E., Ma, A. H., Xia, L., Lee, L. F., Pretlow, T. G., & Kung, H-J. (2002). Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line. Cancer Research, 62(22), 6606-6614.